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CAS No. : | 1308298-23-8 | MDL No. : | MFCD10696932 |
Formula : | C5H4BF3N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OEZMIKKBMMAABO-UHFFFAOYSA-N |
M.W : | 191.90 | Pubchem ID : | 55263556 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 7.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 36.86 |
TPSA : | 66.24 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.45 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.03 |
Log Po/w (WLOGP) : | 0.33 |
Log Po/w (MLOGP) : | -1.01 |
Log Po/w (SILICOS-IT) : | -0.5 |
Consensus Log Po/w : | -0.23 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.26 |
Solubility : | 10.6 mg/ml ; 0.0552 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.97 |
Solubility : | 20.4 mg/ml ; 0.106 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.43 |
Solubility : | 7.08 mg/ml ; 0.0369 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.81 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.2% | With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2 h; Inert atmosphere | To a solution of 5-bromo-2-(trifluoromethyl)pyrimidine (700.6 mg, 3.1mmol) and(iPrO)3B (1.1 mL, 4.7mmol) in THF (10 mL) was added dropwise n-BuLi (1.7 mL , 2.4M in hexane, 4.0 mmol) at -78oC. The mixture was stirred at the same temperature for 2 h and quenched with water. The solvent was removed under reduced pressure and the residue was extracted with Ether (2 x 40 mL). The aqueous layer was separated, then adjusted to pH 6 with 1N HCl and extracted with EA (3 x 40 mL). Combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the title product (400 mg, 67.2percent yield) as a white solid. Retention time (LC-MS): 0.66 min. MH+ 193 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 120℃; for 0.166667h;Microwave irradiation; | Example 113(2R)-2-[({3-fluoro-6-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl}methyl)amino]-3-methylbutan-1-olA 20 mL microwave vial was charged with <strong>[1308298-23-8]2-(trifluoromethyl)pyrimidin-5-ylboronic acid</strong> (363 mg, 1.889 mmol), Example 73A (500 mg, 1.717 mmol), bis(triphenylphosphine)palladium(II) chloride (60.3 mg, 0.086 mmol), and potassium carbonate (475 mg, 3.43 mmol), followed by the addition of DME (9.0 mL), water (3.86 mL) and ethanol (2.57 mL). The mixture was heated in the microwave at 120° C. for 10 minutes. To the reaction mixture was added 100 mL 1.0 N NaOH, and extracted with 100 mL dichloromethane (2.x.). The combined dichloromethane layers were washed with 1.0 N HCl and partitioned. The resulting aqueous phase was neutralized with 3.0 N NaOH, extracted with EtOAc, and partitioned. The EtOAc layer was washed with brine, separated, dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse phase chromatography. The combined fractions were concentrated. To the resulting residue was added EtOAc, and the solution was washed with 1.0 N NaOH and brine sequentially, and partitioned. The organic phase was dried over Na2SO4, filtered, and concentrated to provide the title compound as a white solid. MS (ESI+) m/z 359.0 (M+H); 1H NMR (300 MHz, DMSO-d6) delta 9.69 (s, 2H), 8.24 (dd, J=8.6, 3.7, 1H), 7.94 (dd, J=9.4, 8.7, 1H), 4.49 (t, J=5.2, 1H), 4.00 (q, J=15.0, 2H), 3.47 (dt, J=10.5, 4.7, 1H), 3.39-3.32 (m, 1H), 2.38 (dt, J=6.9, 4.7, 1H), 1.95-1.74 (m, 1H), 0.86 (t, J=7.1, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 14.0h;Inert atmosphere; Sealed tube; | Example 74 2-[(4-Fluoro-benzenesulfonyl)-isopropyl-amino]-N-[2-(2-trifluoromethyl-pyrimidin-5-yl)- pyridin-4-ylmethyl] -acetamide A solution of (2-bromo-pyridin-4-ylmethyl)-carbamic acid teri-butyl ester (300 mg, 1.04 mmol), 2- (trifluoromethyl)pyrimidin-5-ylboronic acid (200 mg, 1.04 mmol) and potassium carbonate (0.14 g, 1.04 mmol) in DMF (5 mL) at 25°C was purged with nitrogen gas and evacuated three times. The solution was then treated with teira 3s(triphenylphosphine)palladium(0) (60 mg, 52 muiotaetaomicron) and then sealed and heated to 120°C for 14 h. The reaction mixture was cooled to 25°C, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave [2-(2-trifluoromethyl^yrirnidin-5-yl)-pyridin-4-ylmethyl]-carbamic acid tert-butyl ester (50 mg, 14percent) as a brown solid. M+H = 355.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; copper diacetate; caesium carbonate; In 1,4-dioxane; at 80℃; | INTERMEDIATE 57 5-(3-Iodo-lH-pyrazol-l-yl)-2-(trifluorometyl)pyrimidine A solution of 3-iodo-lH-pyrazole (0.7 g, 3.61 mmol), 2-trifluoromethylpyrimidine -4- boronic acid (0.722 g, 4.69 mmol), DMAP (1.763 g, 14.43 mmol), copper(II) acetate (0.655 g, 3.61 mmol), and cesium carbonate (2.94 g, 9.02 mmol) in 1 ,4-dioxane (18.0 mL) was heated at 80 °C overnight. The reaction was allowed to room temperature and filtered. The filtrate was diluted with EtOAc and water, and the seperated aq. layer was extracted with EtOAc. The combined organics were dried over MgS04, filtered and concentrated. The residue was purified with flash chromatography (ISCO Combiflash, 40 g, 0-5 percent EtOAc in hexanes) to give 5-(3-iodo-lH-pyrazol-l-yl)-2- (trifluorometyl)pyrimidine, as a white solid. LCMS calc. = 340.94; found = 340.88 (M+H)+. NMR (500 MHz, CDC13): 8 9.25 (s, 2 H); 7.86 (d, J= 2.5 Hz, 1 H); 6.78 (d, J= 2.7 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 120℃; for 0.5h;Microwave irradiation; Inert atmosphere; | To a microwave vial was added tert-butyl 5-bromo-1-oxo-isoindoline-2-carboxylate 2 (800 mg, 2.6 mmol), [5-(trifluoromethyl)pyrimidin-2-yl]boronic acid (584 mg, 3.1 mmol), potassium carbonate (1.1 g, 7.7 mmol), water (0.5 mL, 30 mmol) and Pd(dppf)C12 (214 mg, 0.26 mmol) in dioxane (5 mL). The reaction mixture was purged with nitrogen gas for 3 minutes and then heated to 120 °C in the microwave for 30 minutes. Upon cooling to room temperature, the resulting mixture was filtered through a thin layer of celite, washed with water and extracted with ethyl acetate. The combined organic layer was dried over Na2504, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate /heptane (1:1) to afford the title compound 3 (700 mg, 72percent) as a white solid. LC/MS (ESI+): mlz 380.3 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.6% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; acetonitrile; at 95℃; for 2.0h;Inert atmosphere; | A solution of 2-(trifluoromethyl)pyrimidin-5 -ylboronic acid (1.2 equiv., 0.3574 mmol), tertbutyl (2S ,4R)-2-[(4-bromo-6-methyl-2-pyridyl)methylcarbamoyl] -4-fluoro-pyrrolidine- 1 -carboxylate (124 mg, 0.2979 mmol), cesium carbonate (194.1 mg, 0.04714 mL, 0.5957 mmol) and [1,1?- bis(diphenylphosphino)feffocene] dichloropalladium(ii) dichloromethane adduct (0.10 equiv., 0.02979 mmol) in acetonitrile (3.0 mL) and water (1.5 mL) was degassed. The reaction mixture was heated at 95 °C for 2h. The reaction was filtered thru celite. The crude product was purified by flash chromatography (MeOH/DCM) to give 70mg, 48.6percent yield. LCMS (ESI) mlz:484.15 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); potassium acetate; sodium carbonate; In water; acetonitrile; at 140℃; for 0.5h;Inert atmosphere; Microwave irradiation; | To a microwave vial was added (25)-N-[(3-bromo-5-fluoro-phenyl)methyl]-4-fluoro-1-(4- fluorophenyl)sulfonyl-4-methyl-pyrrolidine-2-carboxamide (60 mg, 0.12 mmol) , 2- (trifluoromethyl)pyrimidin-5-ylboronic acid (33 mg, 0.17 mmol), bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) (6.9 mg, 0.0098 mmol), sodium carbonate (18 mg, 0.17 mmol) and potassium acetate (17 mg, 0.17 mmol). Acetonitrile (0.8 mL) and water (0.16mL) were added and nitrogen was bubbled through the reaction mixture for 3 mins then heated to 140 °C in the microwave for 30 mins. The reaction mixture was diluted with dichloromethane, filtered through celite, eluting with dichloromethane and the filtrate was concentrated in vacuo. The residue was adsorbed onto silica and purified by flash column chromatography with 0-100percent EtOAc in heptane to afford the partially purified product. The residue was further purified by RP-HPLC to yield the title compound as a white solid (43.3 mg, 68percent). MS-ESI: [M+H] 559.12[0842] ?H NMR (400 MHz, DMSO) 6 9.42 (s, 2H), 8.92 (t, J = 6.0 Hz, 1H), 8.02 ? 7.92 (m, 2H), 7.78 ?7.69 (m, 2H), 7.51 ?7.40 (m, 2H), 7.40?7.32 (m, 1H), 4.56 ?4.38 (m, 2H), 4.25 ?4.16 (m, 1H), 3.71 ?3.46 (m, 2H), 2.48 ?2.31 (m, 1H), 2.15 ? 1.94 (m, 1H), 1.38 (d, J= 20.7 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In water; acetonitrile; at 140℃; for 0.5h;Inert atmosphere; Microwave irradiation; | To a microwave vial was added (1R,45,55)-N-[(5-bromo-2-fluoro-phenyl)methyl]-3-(4- fluorophenyl)sulfonyl-3-azabicyclo[3.1.0]hexane-4-carboxamide 6 (35 mg, 0.07 mmol), [5- (trifluoromethyl)pyrimidin-2-yl]boronic acid (15.7 mg, 0.08 mmol), cesium carbonate 1 M in water (0.10 mL, 0.10 mmol), Pd(dppf)C12 (0.1 equiv., 0.01 mmol) and acetonitrile (0.8 mL). The reaction mixture was purged with nitrogen gas for 3 minutes and then heated to 140 °C in the microwave for 30 minutes. Upon cooling to room temperature, the resulting mixture was filtered through a thin layer of celite, washed with water and extracted with ethyl acetate. The combined organic layer was dried over Na2504, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate/heptane (3:1) to afford the title compound (24 mg, 60percent) as a white solid. HZ/MS (ESI+): m/z 539.2 (M+H).[01979] 1H NMR (400 MHz, DMSO-d6) 6 9.36 (s, 2H), 8.77 (t, J = 5.9 Hz, 1H), 8.02 ? 7.75 (m, 4H), 7.57 ?7.28 (m, 3H), 4.60 ?4.31 (m, 2H), 4.22 (s, 1H), 3.72 (td, J = 9.9, 3.6 Hz, 1H), 3.47 (d, J = 10.4 Hz, 1H), 1.69? 1.40 (m, 2H), 0.60?0.45 (m, 1H), -0.82 (dt, J = 5.1, 4.0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.3% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; acetonitrile; at 95℃; for 2.0h;Inert atmosphere; | A solution of <strong>[1308298-23-8]2-(trifluoromethyl)pyrimidin-5-ylboronic acid</strong> (100 mg, 0.50 mmol), 4,6- dichloropyrimidine (0.742559 mmol), cesium carbonate (322.595 mg, 0.99 mmol) and [1,1?- bis(diphenylphosphino)feffocene] dichloropalladium(ii) dichloromethane adduct (0.10 equiv., 0.050 mmol) in acetonitrile (6.0 ml) and water (3.0 mL) was degassed. The reaction mixture was heated at 95 °C for 2h. The reaction was filtered thru celite. The crude product was purified by flash chromatography (EtOAc/Hex_eluted at 20percentEtOAc) to give 74mg, 57.3percent yield. LCMS (ESI) mlz:260.9 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In water; acetonitrile; at 95℃; for 2.0h;Inert atmosphere; | General procedure: A solution of <strong>[1308298-23-8]2-(trifluoromethyl)pyrimidin-5-ylboronic acid</strong> (100 mg, 0.50 mmol), 4,6- dichloropyrimidine (0.742559 mmol), cesium carbonate (322.595 mg, 0.99 mmol) and [1,1?- bis(diphenylphosphino)feffocene] dichloropalladium(ii) dichloromethane adduct (0.10 equiv., 0.050 mmol) in acetonitrile (6.0 ml) and water (3.0 mL) was degassed. The reaction mixture was heated at 95 °C for 2h. The reaction was filtered thru celite. The crude product was purified by flash chromatography (EtOAc/Hex_eluted at 20percentEtOAc) to give 74mg, 57.3percent yield. ;[02120] Step 4: Following the same Suzuki coupling procedure of Example 42, step 1: The title compound 195 (25,4R)-4-fluoro- 1 -(4-fluorophenyl)sulfonyl-N-[ [5 -[2-(trifluoromethyl)pyrimidin-5 - yl]-3-pyridyl]methyl]pyffolidine-2-carboxamide (62 mg, 54percent) was prepared from (25,4R)-N-[(5- bromo-3 -pyridyl)methyl] -4-fluoro- 1 -(4-fluorophenyl)sulfonyl-pyrrolidine-2-carboxamide (TNT- 195- 4) (100 mg, 0.22 mmol), [5-(trifluoromethyl)pyrimidin-2-yl]boronic acid (46 mg, 0.24 mmol), cesium carbonate 1 M in water (0.3 mL, 0.3 mmol), Pd(dppf)C12 (18 mg, 0.02 mmol) in acetonitrile (1 mL). MS-EST: [M+H] 528.5[02121] ?H NMR (400 MHz, DMSO-d6) 3 9.53 ? 9.37 (m, 2H), 9.07 ? 8.97 (m, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.23 (t, J = 2.2 Hz, 1H), 8.05 ?7.87 (m, 2H), 7.56 ?7.33 (m, 2H), 5.19 (d, J = 52.8 Hz, 1H), 4.63 ?4.33 (m, 2H), 4.25 ?4.09 (m, 1H), 3.78 ? 3.67 (m, 1H), 3.64 (dd, J = 14.9, 2.4 Hz, 1H), 2.49 ?2.28 (m, 1H), 2.07 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34.6% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere; | To a mixture of <strong>[1308298-23-8]2-(trifluoromethyl)pyrimidin-5-ylboronic acid</strong> (173 mg, 0.90mmol)N-(2- bromothiazol-4-yl)acetamide (200 mg, 0.90 mmol) in 1,4-dioxane (4 mL) and H2O (0.8 mL) was added Cs2CO3 (880 mg, 2.70 mmol). The mixture was degassed with N2 for three times. Pd(PPh3)4 (52 mg, 0.045 mmol) was added and the reaction mixture was stirred at 100 oC under N2 overnight. The mixture was cooled down and poured into EA. The organic phase was separated, washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (eluted with DCM: MeOH = 100: 1) to afford N-(2-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-yl)acetamide (90 mg, 34.6percent yield) as a white solid. Retention time (LC-MS) : 1.663 min. MH+ 289. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.2% | With n-butyllithium; In tetrahydrofuran; hexane; at -78℃; for 2.0h;Inert atmosphere; | To a solution of 5-bromo-2-(trifluoromethyl)pyrimidine (700.6 mg, 3.1mmol) and(iPrO)3B (1.1 mL, 4.7mmol) in THF (10 mL) was added dropwise n-BuLi (1.7 mL , 2.4M in hexane, 4.0 mmol) at -78oC. The mixture was stirred at the same temperature for 2 h and quenched with water. The solvent was removed under reduced pressure and the residue was extracted with Ether (2 x 40 mL). The aqueous layer was separated, then adjusted to pH 6 with 1N HCl and extracted with EA (3 x 40 mL). Combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the title product (400 mg, 67.2percent yield) as a white solid. Retention time (LC-MS): 0.66 min. MH+ 193 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.6% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere; | A mixture of (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (420.0 mg, 2.2 mmol)6- chloropyrazin-2-amine (378.3 mg, 2.2 mmol), Pd(PPh3)4 (252.7 mg, 0.2 mmol) and potassium carbonate (604.6 mg, 4.4 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was degassed and stirred at 90oC under N2 overnight. The reaction mixture was cooled down and poured into EA. The organic phase was separated, washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in Ether. The mixture was filtered and the filtrate was concentrated to give the title product (200 mg, 52.6percent yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In tetrahydrofuran; for 0.333333h;Reflux; | General procedure: 80 mg of the aryl bromide prepared in Example 316 together with 32 mg of (5-chloropyridin-2-yl)boronic acid was first placed in 1 ml tetrahydrofuran, treated with 17.3 mg of 1,1'-bis(diphenylphosphino)ferrocenodichloropalladium(II) and 0.17 ml of 1M potassium carbonate solution and heated in the microwave for 10 minutes at 120° C. (100 watts). After fresh addition of 11 mg of (5-chloropyridin-2-yl)boronic acid and 17.3 mg of the palladium(II) catalyst, the reaction mixture was again heated in the microwave for 10 minutes at 120° C. (100 watts) until complete conversion. The reaction mixture was concentrated. After HPLC purification, this yielded 15 mg of the title compound. Analogously to Example 317, 34 mg of the title compound was obtained from 125 mg of 316 and 89 mg of <strong>[1308298-23-8][2-(trifluoromethyl)pyrimidin-5-yl]boronic acid</strong> under reflux. 1H-NMR (400 MHz, DMSO-d6): delta [ppm], 1.21-1.35 (2H), 1.36-1.71 (2H), 2.23-2.41 (1H), 2.54 (3H), 2.71-2.89 (1H), 2.94-3.17 (1H), 3.48-3.72 (1H), 4.05 (2H), 4.28-4.61 (3H), 7.21 (1H), 7.47 (1H), 7.57 (2H), 7.98 (2H), 8.57 (1H), 8.84 (1H), 9.44 (2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In tetrahydrofuran; for 0.333333h;Reflux; | General procedure: 80 mg of the aryl bromide prepared in Example 316 together with 32 mg of (5-chloropyridin-2-yl)boronic acid was first placed in 1 ml tetrahydrofuran, treated with 17.3 mg of 1,1'-bis(diphenylphosphino)ferrocenodichloropalladium(II) and 0.17 ml of 1M potassium carbonate solution and heated in the microwave for 10 minutes at 120° C. (100 watts). After fresh addition of 11 mg of (5-chloropyridin-2-yl)boronic acid and 17.3 mg of the palladium(II) catalyst, the reaction mixture was again heated in the microwave for 10 minutes at 120° C. (100 watts) until complete conversion. The reaction mixture was concentrated. After HPLC purification, this yielded 15 mg of the title compound. Analogously to Example 317, 14 mg of the title compound was obtained from 100 mg of 54 and 56 mg of <strong>[1308298-23-8][2-(trifluoromethyl)pyrimidin-5-yl]boronic acid</strong> under reflux. 1H-NMR (400 MHz, DMSO-d6): delta [ppm], 1.24 (2H), 1.38-1.73 (2H), 2.22-2.41 (1H), 2.53 (3H), 2.70-2.89 (1H), 2.94-3.18 (1H), 3.28 (3H), 3.36-3.43 (2H), 3.44-3.49 (2H), 3.51-3.70 (1H), 4.37 (3H), 7.18 (1H), 7.42 (1H), 7.57 (2H), 7.97 (2H), 8.13 (1H), 8.51 (1H), 9.43 (2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.7% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; acetonitrile; at 95℃; for 2.0h; | [0961] A solution of <strong>[1308298-23-8]2-(trifluoromethyl)pyrimidin-5-ylboronic acid</strong> (92 mg, 0.45 mmol), (1R,45,55)- N-[(2-bromo-5 -fluoro-4-pyridyl)methyl] -6,6-difluoro-3-(4-fluorophenyl)sulfonyl-3- azabicyclo[3.1.0]hexane-4-carboxamide (192 mg, 0.378 mmol), cesium carbonate (246 mg, 0.756 mmol) and [1,1 ?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (31.5 mg 0.0378 mmol) in acetonitrile (3.0 mL) and water (1.5 mL) was degassed. The reaction mixture was then heated at 95 °C for 2 h. The reaction was filtered thru celite, concentrated and purified by flash chromatography (MeOH/DCM eluted at 8percentMeOH). Purification by reversed phase HPLC provided the title compoun(62.7 mg, 27.7percent yield). MS-ESI: [M+H] 576.2[0962] 1H NMR (400 MHz, DMSO) 3 9.61 ? 9.57 (s, 2H), 9.13 ?9.05 (m, 1H), 8.81 ? 8.77 (d, J = 1.3 Hz, 1H), 8.22? 8.16 (d, J = 5.7 Hz, 1H), 7.98 ?7.91 (m, 2H), 7.50? 7.42 (m, 2H), 4.62?4.49 (m, 2H), 4.48 ?4.45 (m, 1H), 3.99 ? 3.89 (m, 1H), 3.69 ? 3.63 (m, 1H), 2.75 ?2.64 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In water; acetonitrile; at 95℃; for 2.0h; | [0973] A solution of <strong>[1308298-23-8]2-(trifluoromethyl)pyrimidin-5-ylboronic acid</strong> (75 mg, 0.370 mmol),(1S,4S ,5R)-N- [(3-bromo-4-fluoro-phenyl)methyl] -3 -(4-fluorophenyl)sulfonyl-6,6-dimethyl-3 -azabicyclo[3.1.0]hexane-4-carboxamide (154 mg, 0.3084 mmol), cesium carbonate (201.0 mg, 0.617mmol) and [1,1 ?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichioromethane adduct (26 mg, 0.03 1 mmol) in acetonitrile (3.0 mL) and water (1.5 mL) was degassed. The reaction mixture was then heated at 95 °C for 2 h. The reaction was filtered through celite and the crude product was purified by flash chromatography (MeOH/DCM). The final product was then purified by reversed phase chromatography to give the title compound (28 mg, 17percent yield). MS-ESI: [M+H] 567.2 1H NMR (400 MHz, DMSO) 3 9.29 ? 9.24 (d, J = 1.3 Hz, 2H), 8.80 ? 8.74 (m, 1H), 7.87 ?7.81 (m, 2H), 7.72?7.67 (m, 1H), 7.55 ?7.48 (m, 1H), 7.47 ?7.37 (m, 3H), 4.45 ?4.30 (m, 2H), 4.10 ?4.03 (s, 1H), 3.70? 3.62 (m, 1H), 3.23 ? 3.17 (m, 1H), 1.54? 1.46 (m, 1H), 1.38 ? 1.30 (d, J = 7.6 Hz, 1H), 0.96 ? 0.90 (s, 3H), 0.58 ? 0.50 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 0.75h;Inert atmosphere; Microwave irradiation; | [013141 Ethyl 5-bromo-2-(trifluoromethyl)pyridine-3-carboxylate (1.00 g, 3.35 mmol, 1.0 equiv.), [2- (trifluoromethyl)pyrimidin-5-yl]boronic acid (772 mg, 4.03 mmol, 1.2 equiv.), Pd(dppf)C12 (248 mg, 0.34 mmol, 0.1 equiv.) and K2C03 (937 mg, 6.71 mmol, 2 equiv.) were charged in a microwave vial and purged under nitrogen. Degassed 1,4-dioxane (17 mL) and water (1.7 mL) was added and the mixture was stirred for 45 mm at 80 °C in the microwave. Reaction mixture was filtered through diatomaceous earth and washed with iPrOAc. The filtrate was partitioned with water and extracted with iPrOAc (3x). The combined organic extracts were washed with brine, dried over Mg504, filtered and concentrated. The crude mixture was purified by a silica gel colunm eluting with iPrOAc/heptane (0-40percent) to afford the title compound (1.20 g, 98percent) as a white solid. LCMS [M+H+]366. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; In toluene; at 100℃;Inert atmosphere; | [01193] A mixture of tert-butyl N- [(tert-butoxy)carbonyl] -N- [(5-chloro-2-cyclopropylpyridin-3 - yl)methyl]carbamate (600 mg, 1.56 mmol, 1.00 equiv), <strong>[1308298-23-8][2-(trifluoromethyl)pyrimidin-5-yl]boronic acid</strong> (515 mg, 2.68 mmol, 1.71 equiv), Pd2(dba)3.CHC13 (163 mg, 0.15 mmol, 0.10 equiv), SPhos (129 mg, 0.31 mmol, 0.20 equiv), and K3P04 (1 g, 4.71 mmol, 3.00 equiv) in toluene (15 mL) was stirred for overnight at 100°C under N2. The solid was filtered out and the filtrate was concentrated under vacuum. The residue was purified by a silica gel colunm eluting with ethyl acetate/petroleum ether (1/4) to afford the title compound (250 mg, 32percent) as yellow oil. LCMS [M+H] 495. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 80℃; for 12.0h;Inert atmosphere; | [01200] A mixture of 4-chloro-5-(difluoromethyl)-2-methylpyridine (600 mg, 3.37 mmol, 1.00 equiv), <strong>[1308298-23-8][2-(trifluoromethyl)pyrimidin-5-yl]boronic acid</strong> (716 mg, 3.73 mmol, 1.10 equiv), Pd(dppf)C12 (248 mg, 0.33 mmol, 0.10 equiv), potassium carbonate (1.4 g, 10.13 mmol, 2.99 equiv), and dioxane (20 mL) was stirred for 12 h at 80°C under nitrogen. The solid was filtered off and the filtrate was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel colunm eluting with petroleum ether/ethyl acetate (10/1) to afford the title compound (610 mg, 62percent) as a brown solid. LCMS [M+H] 290. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.4 mg | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); potassium acetate; sodium carbonate; In water; acetonitrile; at 120℃; for 0.25h;Microwave irradiation; Inert atmosphere; | To a microwave vial was added N-[(3-bromo-5-fluoro-phenyl)methyl]-3-(4- fluorophenyl)sulfonyl-3-azabicyclo[2.1.1]hexane-2-carboxamide (65 mg, 0.14 mmol) , 2- (trifluoromethyl)pyrimidin-5-ylboronic acid (38 mg, 0.19 mmol), bis(di-terf-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) (7.8 mg, 0.01 1 mmol), sodium carbonate (20 mg, 0.19 mmol) and potassium acetate (19 mg, 0.19 mmol). Acetonitrile (1.5 mL) and water (0.30 mL) were added and nitrogen was bubbled through the reaction mixture for 3 mins then heated to 120 °C in the microwave for 15 mins. The reaction mixture was diluted with dichloromethane, filtered through celite, eluting with dichloromethane and the filtrate was concentrated in vacuo. The residue was adsorbed onto silica and purified by flash column chromatography with 0-100percent EtOAc in Heptane to afford the desired compound as a yellow foam. The residue was further purified by Chiral SFC to yield the title compound (28.4 mg, 38percent) as a white solid. LCMS [M+H+] 547.1 ; NMR (400 MHz, DMSO-J6) delta 9.43 (s, 2H), 8.73 (t, J= 6.1 Hz, 1H), 8.02 - 7.94 (m, 2H), 7.77 - 7.68 (m, 2H), 7.54 - 7.44 (m, 2H), 7.36 - 7.27 (m, 1H), 4.55 (dd, J= 16.0, 6.5 Hz, 1H), 4.41 (dd, J= 15.9, 5.8 Hz, 1H), 4.26 - 4.18 (m, 1H), 3.95 (s, 1H), 2.85 - 2.76 (m, 1H), 1.91 - 1.86 (m, 1H), 1.84 - 1.77 (m, 1H), 1.75 - 1.67 (m, 1H), 0.49 - 0.39 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In water; acetonitrile; at 110℃; for 0.5h;Microwave irradiation; Inert atmosphere; | To a microwave vial was added terf-butyl 3-(((2-bromo-6-chloropyridin-4- yl)methyl)carbamoyl)-2-azabicyclo[2.1.1 ]hexane-2-carboxylate ( 1 18 mg, 0.27 mmol), 2- (trifluoromethyl)pyrimidin-5-ylboronic acid (52 mg, 0.27 mmol) and 1 , 1 '- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1 8 mg, 0.022 mmol). Acetonitrile (3.6 mL) and 1 M potassium acetate in water (0.9 mL, 0.9 mmol) were added and nitrogen was bubbled through the reaction mixture for 3 mins then heated to 1 10 °C in the microwave for 30 min. The reaction mixture was diluted with dichloromethane, filtered through celite, eluting with dichloromethane and the filtrate was concentrated in vacuo. The residue was adsorbed onto silica and purified by flash column chromatography with 0-10percent MeOH in DCM to afford the desired compound as a brown foam ( 1 1 8 mg, 87percento). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 70℃; for 3.0h;Inert atmosphere; | Into a 3000-mL 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed 2-[(6-chloropyrimidin-4-yl)methyl]-2,3-dihydro-lH-isoindole- 1,3-dione (50 g, 182.70 mmol, 1.00 equiv), 1,4-dioxane (1500 mL), water (70 mL), potassium carbonate (50 g, 361.77 mmol, 2.00 equiv), <strong>[1308298-23-8][2-(trifluoromethyl)pyrimidin-5-yl]boronic acid</strong> (91 g, 474.20 mmol, 2.50 equiv), and Pd(dppf)Cl2 (4 g, 5.47 mmol, 0.02 equiv). The resulting solution was stirred at 70°C for 3 h, cooled to room temperature, quenched by the addition of 3 L of water, and extracted with 3x1 L of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1 : 10) to afford 55 g (78percent) of 2-([6-[2- (trifluoromethyl)pyrimidin-5-yl]pyrimidin-4-yl]methyl)-2,3 -dihydro- 1 H-isoindole- 1 ,3 -dione as a white solid. LCMS [M+H]+ 386. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.22 g | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In acetonitrile; at 80℃; for 20.0h;Inert atmosphere; | A mixture of intermediate 1.5 (2.3g), <strong>[1308298-23-8]2-(trifluoromethyl)pyrimidine-5-boronic acid</strong> (1.65g), Pd(PPh3)2CI2 (202mg), 1 M Na2C03 (15mL) in MeCN (15mL) was vigorously stirred at 80°C under argon for 20h. The reaction mixture was allowed to cool down to RT, diluted with H20 and extracted with DCM (3x). The combined org. layers were dried over MgSCU, filtrated off and evaporated to dryness. The crude was purified by CC (Biotage, SNAP 340g cartridge, solvent A: Hep; solvent B: EA; gradient in percentB: 10 for 5CV, 10 to 30 over 6CV, 30 for 3CV) to afford 2.22g (Cpd1 ) as yellow foam. LC-MS (A): tR = 0.97min; [M+H]+: 514.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 4.0h;Inert atmosphere; | To a solution of 113 5-iodo-7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Preparation 33, 43 g, 110 mmol), 114 2-(trifluoromethyl)pyrimidin-5-yl boronic acid (36.2 g, 132 mmol) in 115 1,4-dioxane (220 mL) at rt was added 116 K2CO3 (30 g, 217 mmol) in 33 H2O (40 mL) and 117 PdCl2(dppf) (8.1 g, 11.1 mmol) under N2 and the reaction stirred at 100° C. for 4 hrs. The cooled reaction was filtered and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with pet. ether:81 EtOAc (50:50) to afford the 91 title compound (38 g, 84percent) as a yellow solid. 1HNMR (400 MHz, DMSO-d6): 0.00 (s, 9H), 0.93 (t, 2H), 3.64 (t, 2H), 5.64 (s, 2H), 6.73 (br s, 2H), 7.88 (s, 1H), 8.31 (s, 1H), 9.13 (s, 2H). LCMS m/z=411.1[MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere; | General procedure: A mixture of the appropriate iodo starting material (1 eq), boronic acid or ester (1.5-2.0 eq), Pd(dppf)Cl2 (0.1 eq) and K2CO3 (1-3 eq) in dioxane:H2O (4:1 v/v) was degassed with N2. The reaction mixture was stirred at 90° C. under N2 for 2-4 hr. The cooled mixture was poured into water and extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere; | General procedure: A mixture of the appropriate iodo starting material (1 eq), boronic acid or ester (1.5-2.0 eq), Pd(dppf)Cl2 (0.1 eq) and K2CO3 (1-3 eq) in dioxane:H2O (4:1 v/v) was degassed with N2. The reaction mixture was stirred at 90° C. under N2 for 2-4 hr. The cooled mixture was poured into water and extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 5.0h; | Step 1: To a solution of 214 N?-(7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide (Preparation 214 60, 500 mg, 1.02 mmol) in 115 dioxane (10 mL) was added 33 H2O (2 mL), 114 2-(trifluoromethyl) pyrimidin-5-ylboronic acid (391 mg, 2.04 mmol), 117 PdCl2(dppf) (75 mg, 0.102 mmol) and 116 K2CO3 (282 mg, 2.04 mmol) and the reaction stirred at 100° C. for 5 hr under N2. The cooled mixture was filtered and the filtrate concentrated. The residue was diluted with EtOAc (150 mL) the solution washed with brine (2×150 mL), dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel eluting with MeOH:DCM (1:20) to give 515 N?-(7-((1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-(2-(trifluoromethyl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethylformimidamide as a yellow solid (300 mg, 57percent). LCMS m/z=511.2 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl-formamide; at 100℃; for 18.0h; | To a solution of 1-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]propyl}-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Preparation 58, 0.3 g, 0.45 mmol) in DMF (25 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine (355 mg, 0.90 mmol) and Na2CO3 solution (7 mL). Pd(PPh3)4 (52 mg, 0.045 mmol) was added and the reaction stirred at 100° C. for 18 hrs. The cooled mixture was partitioned between EtOAc and water and the layers separated. The organic layer was washed with brine, dried and evaporated in vacuo. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (95:5) to afford the title compound (170 mg, 78percent). LCMS m/z=484.1 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 2.0h;Inert atmosphere; | A stirred solution of 1-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Preparation 59, 3 g, 6.46 mmol) in dioxan/H2O (100 mL/25 mL) was added <strong>[1308298-23-8]2-(trifluoromethyl)pyrimidin-5-ylboronic acid</strong> (1.86 g, 9.69 mmol), K2CO3 (2.67 g, 19.38 mmol) and Pd(dppf)Cl2 (236 mg, 0.323 mmol) under N2 and the reaction stirred at 90° C. for 2 hrs. The cooled mixture was filtered, the filtrate concentrated under reduced pressure and the residue diluted with water and extracted with EtOAc (3×100 mL). The combined organic extracts were concentrated in vacuo and purified by prep HPLC to give the title compound as a yellow solid (1.6 g, 51percent). 1HNMR (400 MHz, DMSO-d6): 0.85 (t, 3H), 2.44 (m, 2H), 6.18 (m, 1H), 7.40 (m, 3H), 7.59 (m, 2H), 7.77 (m, 1H), 8.35 (s, 1H), 8.65 9s, 1H), 9.27 (s, 2H). LCMS m/z=484.7 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 105℃; for 2.0h;Inert atmosphere; | To a solution of 5-bromo-7-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine (Preparation 1, 500 mg, 1.27 mmol) in 1,4-dioxane (10 mL), was slowly added <strong>[1308298-23-8]2-(trifluoromethyl)pyrimidin-5-ylboronic acid</strong> (867 mg, 4.52 mmol), K2CO3 (356 mg, 2.58 mmol) in H2O (5 mL) and Pd(dppf)Cl2 (105 mg, 0.129 mmol) and the reaction stirred at 105° C. for 2 hrs under N2. The cooled mixture was concentrated in vacuo and the crude product purified by column chromatography on silica gel eluting with DCM:MeOH (91:9) to afford the title compound as a yellow solid (260 mg, 44percent). LCMS m/z=456.1 [MH]+; RT [HPLC Method A]=1.717 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 25 - 80℃; for 2.0h;Large scale; | Compound 1(a) (5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4- yl)methanol was prepared from compound l0C(i) (2-chloro-5-methylpyridin-4-yl)methanol and compound 8 2-(trifluoromethy l)pyrimi din-5 -ylboronic acid as follows:,4-dioxane (52.73 kg, 7.22 kg/kg compound l0C(i)) and water (36.5 kg, 5 kg/kg compound l0C(i)) was charged into a first inerted, stirred reactor and stirred. Potassium carbonate (11.9 kg, 1.63 kg/kg compound l0C(i)) was charged into the first reactor followed by compound lOC(i) (7.3 kg, 93 moles). The temperature of the mixture was adjusted to 25-30 C and the first reactor was further charged with [l,l?-Bis(diphenylphosphino) ferrocene] palladium (II) chloride (0.505 kg, 0.07 kg/kg compound l0C(i)). Nitrogen was bubbled through the solution for 1-2 hours before the solution was heated to 75-80 C and stirred for 2 hours.The first reactor contents were sampled and tested for compound l0C(i) content by HPLC Method-011. Sampling and LC testing was continued (with 30 minute intervals) until the compound l0C(i) content was less than 5.0%.The reaction mixture was cooled to 45 C and the first reactor contents was distilled under reduced pressure in order to reach a volume of 3 L/kg while maintaining the temperature of the reactor below 60 C. Water was charged (58.4 kg, 8.0 kg/kg compound 2C) into the first reactor followed by methyl tert-butyl ether (54 kg, 7.4 kg/kg compound l0C(i)) and the mixture was stirred for at least 10 minutes. Agitation was stopped and the mixture was allowed to settle for at least 10 minutes. The bottom aqueous layer was removed and transferred to a first vessel and the organic layer was drained to a second vessel. The aqueous phase was charged to the first reactor followed by methyl /-butyl ether (27 kg, 3.7 kg/kg compound l0C(i)) and the mixture was stirred for at least 10 minutes. Agitation was stopped and mixture was allowed to settle for at least 10 minutes. The bottom aqueous layer was removed and transferred to the first vessel and the organic layer was drained to the second vessel. The aqueous phase was charged to the first reactor followed by methyl /-butyl ether (27 kg, 3.7 kg/kg compound l0C(i)) and the mixture was stirred for at least 10 minutes. Agitation was stopped and mixture was allowed to settle for at least 10 minutes. The bottom aqueous layer was removed and transferred to the first vessel.The organic phase in the second vessel was charged into the first reactor followed by silica gel (3.65 kg, 0.50 kg/kg compound l0C(i)), and the reactor contents was stirred for at least 2 hours at 25-30 C. The reactor contents were filtered, and the filtrate was collected in a third vessel. The first reactor was rinsed with methyl /-butyl ether (27 kg, 3.7 kg/kg compound l0C(i)) which was then filtered through the filter cake and collected in the third vessel. The filtrate in the third vessel was charged into a second reactor.The contents of the second reactor were distilled under reduced pressure in order to reach a volume of 2 L/kg while maintaining the temperature of the reactor below 50 C. Heptane (25 kg, 3.42 kg/kg compound l0C(i)) was charged into the second reactor and the contents of the second reactor were distilled under reduced pressure in order to reach a volume of 4 L/kg while maintaining the temperature of the reactor below 50 C. Charging the second reactor with heptane and distilling the reactor contents as described was repeated two more times. The second reactor was then charged with dichloromethane (14.56 kg, 2.0 kg/kg compound l0C(i)) and the mixture was stirred for at least 2 hours at 25-30 C. The contents of the second reactor were filtered and the filter cake and reactor was washed with a mixture of dichloromethane (3.24 kg, 0.44 kg/kg compound l0C(i)) and heptane (3.32 kg, 0.45 kg/kg compound l0C(i)). The filter cake was dried under vacuum at 30-40 C for 14 hours to give crude compound 1(a) (-10 kg). Dichloromethane was charged (26.6 kg, 3.64 kg/kg compound l0C(i)) into an inerted third reactor, followed by the crude compound 1(a) (-10 kg). The reactor contents were heated to 35-45 C and stirred for at least 2 hours. Heptane was charged (27.36, 3.75 kg/kg compound l0C(i)) into the third reactor over a period of 3 hours. The mixture was cooled to 20-30 C and this temperature was held for at least 2 hours. The solids were filtered and filter cake was washed with a mixture of dichloromethane (4.44 kg, 0.61 kg/kg compound l0C(i)) and heptane (4.55 kg, 0.62 kg/kg compound l0C(i)). The solids were dried in a vacuum oven at 30-40 C for at least 14 hours to give compound 1(a) (8.53 kg, 78% yield). The purity of the product was determined to be 98.71 A% using analytical HPLC Method-Ol l. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Water (7 kg, 0.28 kg/kg compound 8B) as a solution in THF (22.4 kg, 0.88 kg/kg compound 8B) was added to the reaction product mixture with stirring while maintaining the temperature -55 to -65 C, and the reaction product mixture was held at that temperature for at least 30 minutes with stirring. The reaction product heated to 0 C over 1-2 hours and then water (376 kg, l3kg/kg compound 8B) was combined with the reaction product mixture while maintaining the temperature under 10 C and the reaction product mixture was maintained under those conditions for at least 30 minutes. The admixture was allowed to settle for at least 10 minutes and the bottom aqueous layer comprising compound 8 was removed. The aqueous layer was admixed with MTBE (93.2 kg, 3.7 kg/kg compound 8B) and stirred for at least 10 minutes. The admixture was allowed to settle for at least 10 minutes and the bottom aqueous layer comprising compound 8 was removed. The pH of the aqueous layer was adjusted to 1 to 2 at a temperature of less than 25C with concentrated The pH-adjusted aqueous phase was admixed with MTBE (93.2 kg, 3.7 kg/kg compound 8B) and stirred for at least 10 minutes. The admixture was allowed to settle for at least 10 minutes and the bottom aqueous layer was removed leaving an organic layer comprising compound 8. The aqueous layer was admixed with MTBE (93.2 kg, 3.7 kg/kg compound 8B) and stirred for at least 10 minutes, the admixture was allowed to settle for at least 10 minutes, and the bottom aqueous layer was removed. The aqueous layer was step was repeated and the aqueous layer was discarded. The organic layers were combined in a reactor and distilled under reduced pressure at a temperature of less than 45 C to reduce the volume to about 3 L/kg compound 8B. l,4-dioxane (130.16 kg, 5.17 kg/kg compound 8B) was charged to the reactor with stirring and the rector contents were distilled under reduced pressure to reduce the volume to about 3 L/kg compound 8B. The reactor contents were cooled to 25 C to yield a solution of compound 8 in l,4-dioxane (71.3 kg, 82% yield). The assay was determined to be 24.5 w/w % compound 8. |
Tags: 1308298-23-8 synthesis path| 1308298-23-8 SDS| 1308298-23-8 COA| 1308298-23-8 purity| 1308298-23-8 application| 1308298-23-8 NMR| 1308298-23-8 COA| 1308298-23-8 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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